Animal feed and process

ABSTRACT

AN ANIMAL FEED PROVIDING INCREASED PRODUCTIVITY AND FEED EFFICIENCY COMPRISING A COMPOUNDS OF THE GROUP CONSISTING OF A 3-ALKYL-7-PHENYLPYRIMIDO(1,2-A)(1,4)BENZODIAZEPIN-1(5H)-ONE OF THE FORMULA:   1-(X=),2-R6,3-(R6-CH2-),5-R1,7-(R2,R3-PHENYL),R4,R5-   1,5-DIHYDROPYRIMIDO(1,2-A)-1,4-BENZODIAZEPINE   WHEREIN R1 IS HYDROGEN, ALKYL OF 1 TO 3 CARBON ATOMS, INCLUSIVE, HYDROXY OR ACETOXY; WHEREIN R2, R3, R4 AND R5 IS HYDROGEN, HALOGEN, NITRO, CYANO, TRIFLUOROMETHYL, SULFONAMIDO, AMINO, ALKYL, ALKOXY, ALKYLTHIO, ALKYLSULFINYL, ALKYLSULFONYL, ALKANOYLAMINO OR DIALKYLAMINO IN WHICH THE CARBON MOIETY IS OF 1 TO 3 CARBON ATOMS, INCLUSIVE, PER ALKANE RADICAL; WHEREIN R6 IS HYDROGEN, ALKYL DEFINED AS ABOVE, PHENYL OR BENZYL; AND WHEREIN X IS OXYGRN SULFUR OR =NH, AND THEIR PHARMACEUTICALLY ACCEPTABLE ACID ADDITION SALTS IN COMBINATION WITH THE NUTRIENT FEED.

United States Patent 3,803,313 ANIMAL FEED AND PROCESS Robert J. Collins, Portage, Mich., assignor to The Upjohn Company, Kalamazoo, Mich. No Drawing. Filed Aug. 9, 1971, Ser. No. 170,341 Int. Cl. A61k 27/00 US. Cl. 424-251 6 Claims ABSTRACT OF THE DISCLOSURE An animal feed providing increased productivity and feed efficiency comprising a compound of the group consisting of a 3-alkyl-7 phenylpyrimido[1,2-a] [1,4]benzodiazepin-1[5H]-one of the formula:

R. CHgR.

N 10 /11 R: l 5 B, R

CROSS REFERENCE TO RELATED APPLICATIONS This application is related to copending United States application Ser. No. 140,238, filed May 4, 1971, which discloses compounds of the Formula 1 and methods for their preparation. The application is now US. Pat. No. 3,734,912, issued May 22, 1973.

BRIEF SUMMARY OF THE INVENTION Broadly the present invention encompasses a nutritionally adequate animal feed having dispersed there in a compound of the Formula 1 in sufiicient concentration to provide increasing productivity and feed efiiciences in healthy meat-producing, milk-producing or egg-laying animals. The invention also includes the process of feeding the composition to meat-producing, milk-producing or egglaying animals.

DETAILED DESCRIPTION It has been found in recent years that meat-producing animals will gain more weight and gain it faster when various classes of compounds such as vitamins, minerals, estrogens, antibiotics, and transquilizers are added to the diet. Although the present available compounds are useful, new materials are still being sought that would produce weight gains more rapidly, to a greater extent, more efiiciently with respect to feed intake at a lower cost and without undesirabl side effects.

It is now possible by use of the present invention to obtain unexpected results in the feeding of meat-producing, milk-producing, or egg-laying animals; that is to say, an increased rate of weight gain, an increased amount of weight gain, an increase in milk production, or increased rate of egg laying, as well as increased feed efiiciency, can

be obtained by the addition of minute quantities of a compound of the Formula 1 to the animals usual nutrient feed.

Compounds of the Formula 1 can be prepared by methods disclosed in United States application Ser. No. 140,238, filed May 4, 1971, now US. Pat. 3,734,912.

Unless otherwise specified, all percentages are given on a weight-to-weight basis. The pound (1b.) weights given are avoirdupois units.

Feeding of the compositions of the present invention can commence for birds shortly after hatching and in the case of mammals, during the creep-feeding period of suckling animals when they are starting on solid food and, of course, after weaning. Feeding of the compositions is continued throughout the growing period, lactation period, or egg-laying period.

The total concentration of the compound of the Formula 1 in the feed composition is determined with regard to the species of animal, age, weight, and average amount of feed consumed daily. Preferably the compound of the Formula 1 is employed in the finished feed that will supply the animal with a daily intake of from about 0.015 mg. to about 250 mg. per head per day.

The following table illustrates the range of compound of Formula 1 in milligrams daily dose per head per day for representative animals.

Range daily dose/ head, mg.

Animal Swine (birth to 8 weeks) dose, mg.

g Turkeys (gr Beef cattle nu m nipe? coo-a ave The foregoing dosage can generally be accomplished by providing from about 125 mg. to about 12,500 mg. of a compound of the Formula 1 per ton of finished feed.

Advantageously a compound of the Formula 1 is sup plied in the form of a liquid or solid premix wherein the concentration is -2000 times greater than the desired final concentration of the feed. For example, the compound of Formula 1 can be dissolved or suspended in a fluid vehicle such as corn oil, cottonseed oil, molasses, distillers solubles and the like to prepare a fluid premix. Alternaitvely, a solid premix can be prepared by mixing a compound of the Formula 1 with an edible solid diluent such as sucrose, lactose, starch, corn meal, flour, calcium carbonate, soybean meal and the like.

EXAMPLE 1 Ground car com Alfalfa meal Soybean oil meal 44% Ground limestone Salt 0.6 Trace mineral mixture 0.05

Contai-ns the following percent of minerals: Mn, 12; Co, 0.08; Fe, 5.0 Cu, 0.4; I, 0.24 Zn, 0.7.

The above feed to be mixed, pelleted and offered to fattening lambs free-choice in conjunction with hay.

To 999 parts of the preceding feed is added 1 part of a premix composition prepared by mixing 0.7 gm. of 9- chloro 3-methyl-7-phenylpyrimido[1,2-a] [1,4]benzodiazepin-1(5H)-one with sufiicient corn meal to make one pound.

The feeding composition so prepared supplies 0.7 mg. of 9-chloro-3-methyl-7-phenylpyrimido[1,2-a] [1,4]benzodiazepin-1(5H)-one per pound or 1.55 parts per million.

The foregoing composition is usefully fed to lambs for increased rate of weight gain and improved utilization Consisting of 16.0 gm. Vitamin A supplement (10 units/ mg.); 3.6 gm. Vitamin D! supplement (15,000 units/gm.); 7.1 gm. riboflavin supplement (1 gm. riboflavin per ounce) 500 mg. niacin.

To 999 parts of the preceding feed is added 1 part of a premix composition prepared by mixing 1.0 gm. of 9- chloro 3 methyl 7 phenylpyrimido[l,2-a] [1,4]benzodiazepin-1(5H)-one with suflicient soybean mill feed to make 1 pound.

The feeding composition so prepared supplies 1.0 mg. of 9-chloro-3-methyl-7-pheny1pyrimido 1,2-a] [1,4] benzodiazepin-1(5H)-one per pound, or about 2.2 parts per million.

The foregoing composition is usefully fed to chickens for increased rate of weight gain and improved utilization of feed. Similarly the composition can be fed to turkeys, ducks and geese.

EXAMPLE 3 A fattening feed for 800 pound yearling cattle is prepared from the following types and amounts of ingredients:

Percent Ground ear corn 89.75 Soybean oil meal, 44% 9.0 Ground limestone 0.7

Salt 0.5

Trace mineral mixture 1 0.05

Contains the following percent of minerals: Mn 12 Co 0.08;Fe, 5.0; Cu, 0.4 I, 0.24 Zn, 0.7.

To 999 parts of the preceding feed is added 1 part of a premix composition prepared by mixing 1.5- gm. of 9-chloro 3 methyl-7-phenylpyrimido[1,2-a] [1,4] benzodiazepin-1(5H)-one with sufiicient wheat flour to make 1 pound.

The feeding composition so prepared supplies 1.5 mg. of 9-chloro-3-methyl-7-phenylpyrimido[1,2-a] 1,4]benzodiazepin-1(5H)-one per pound, or about 3.3 parts per million.

Cattle are to receive the foregoing feed ad libitum together with 5 lb. of hay per head per day and when so (fed have an increased rate of weight gain and improved utilization of feed.

4 EXAMPLE 4 A swine diet for growing hogs of 40 to pounds body weight is prepared from the following types and amounts of ingredients:

1 Contains the following percent of minerals: Mn, 12; Co,

0.08; Fe, 5.0; Cu, 0.4; I, 0.24, Zn

2 Contains 30o USP units Ds/Gm.'and 1500 I.U.A./Gm.

Contains per 1b.: Riboflavin, 2000 mg.; calcium pantoilaegggeinmm mg.; niacin, 9000 mg.; and choline chloride conta iiis 6 mg. Vitamin B12 per lb.

To 999 parts of the preceding feed is added 1 part of a premix composition prepared by mixing 0.7 gm. of 9- chloro 3 methyl-7-phenylpyrimido[1,2-a] [1,4] benzodiazepin-l(5H)-one with sufficient ground limestone to make one pound.

The feeding composition so prepared supplies 0.7 mg. of 9-chloro-3-methyl-7-phenylpyrimido[1,2-a] [1,4] benzodiazepin-1(5H)-one per pound, or about 1.65 parts per million.

The foregoing composition is usefully fed to hogs for increased rate of weight gain and improved utilization of feed.

EXAMPLE 5 Following the procedure of the preceding examples 1 to 4, inclusive, animal feeds are similarly prepared substituting equimolar amounts of:

9-chloro-3-methyl-7-pheuylpyrimido 1,2-a] 1,4] benzodiazepin-l 5H) -thione;

9-chloro-3-methyl-7-phenylpyrimido 1,2-a] 1,4] benzodiazepin-l (5H)-imine;

9-chloro-3 -methyl-7-phenylpyrimido 1,2-a] 1,4 benzodiazepin-l 5H) -one-6oxide;

9-ch1oro-5-hydroxy-3-methyl-7-phenylpyrimido 1,2-a]

[1,4]benzodiazepin-1(5H)-one acetate;

9-chloro-5-hydroxy-3-methyl-7-phenylpyrimido 1,2-a]- [1,4]benzodiazepin-1 (5H)-one;

9-chloro-3-methyl-7- (o-chlorophenyl) pyrimido[ 1,2-a]

[1,4] benzodiazepin-l (5H)-one;

9-nitro-3-methyl-7-phenylpyrimido 1,2-a] 1,4] benzodiazepin-l (5 H) -one;

9-fiuoro-3-methyl-7-phenylpyrimido 1,2-a] 1,4] benzodiazepin-1(5H)-one;

9-chloro-3 -ethyl-2-methyl-7- 2,6-difiuorophenyl) pyrimido 1,2-a] [1,4]benzodiazepin-1(5H)-one;

9,10-dicyano-3-butyl-2-propyl-7-[p-(methylsulfonyl)- phenyi]pyrimido[1,2-a] [1,4]benzodiazepin-1(5H)- one;

3-benzyl-2-phenyl-9, 1 l-bis (dipropylamino -7- (o-nitrophenyl)pyrimido[1,2-a] [1,4]benzodiazepin-1(5H)- one;

3-phencthyl-2-benzyl-8-chloro-7- (m-bromophen'yl) pyrimido[1,2-a] [1,4]benzodiazepin-1 (5H)-one;

3-propyl-2-ethyl-9-methylsulfinyl-7- (o-fluorophenyl) pyrimido 1,2-a] 1,4] benzodiazepin- 1 (5H) -one;

3,5 ,8, 10-tetramethyl-7- (o-chlorophenyl) pyrimido[ 1,2-

a]-[1,4] benzodiazepin-1(5H)-one;

3-benzyl-2-phenyl-1 1-trifluoromethy1-7- [p- (propionylamino phenyl] pyrimido[ 1,2-a] 1,4] benzodiazepin- 1 (5H) -one;

3-benzyl-2-phenyl-l 1-trifluoromethyl-7- [p- (propionylamino) phenyl] pyrimido[ 1,2-a] 1,4]benzodiazepin- 1 (5H) -thione;

UNITED STATES PATENT OFFICE CERTIFICATE OF CORRECTION Patent No. 3,803,313 Dated April 9-, I974" Inventor(s) Robert J C01 1 inS It is certified that error appears in the above-identified patent and that said Letters Patent are hereby corrected as shown below:

Column l line 61 "transquilizers'" should read "tranquilizers"; line 62, "present" should read --presently--. Column 2, line 50, "Alternaitvely" Should read -Alternat1'vely--. Column 5, line 22, "benzoidazepin" should read -benzodiazepin-; line 42, "phenylpyrimid" should read -phenylpyr1mido--. Column 6, lines l9-23, the formula should read R CH R xi b, I

Signed and sealed this 18th day of March 1975.

'(SEAL) Attest:

C. MARSHALL DANN RUTH C. MASON Commissioner of Patents Attesting Officer and Trademarks 

